ω-Aryl-PGD compounds

ABSTRACT

Prostaglandin analogs with the following cyclopentane ring structure: ##STR1## are disclosed along with intermediates useful in their preparation and processes for their preparation. These analogs are useful for the same pharmacological purposes as the prostaglandins, particularly and especially as blood platelet aggregation inhibitors.

The present application is a divisional application of Ser. No. 614,242, filed Sept. 17, 1975, now issued as U.S. Pat. No. 4,016,184, on Apr. 5, 1977.

The present invention relates to prostaglandin analogs for which the essential material constituting a disclosure therefor is incorporated by reference here from U.S. Pat. No. 4,016,184, issued Apr. 5, 1977. 

I claim:
 1. A prostaglandin analog of the formula ##STR2## wherein D is ##STR3## wherein Y is cis-CH═CH--, trans-CH═CH--, or --CH₂ CH₂ --; wherein Z₁ is
 1. cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --,2.
 2. cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂,3. cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --,
 4. --(CH₂)₃ --(CH₂)_(g) --CF₂ --,
 5. --(CH₂)₃ --(CH₂)_(g) --CH₂ --,
 6. --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --,
 7. --(CH₂)₂ --O--(CH₂)_(g) --CH₂ --,
 8. --(CH₂)₃ --O--(CH₂)_(g) --, ##STR4## wherein g is one, 2, or 3; wherein M₁ is ##STR5## wherein R₅ and R₆ are hydrogen or methyl, with the proviso that one of R₅ and R₆ is methyl only when the other is hydrogen;wherein L₁ is ##STR6## or a mixture of ##STR7## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein Z₃ is oxa or methylene: wherein T is chloro, fluoro, trifluoromethyl, alkyl of 1 to 3 carbon atoms, inclusive, or alkoxy of 1 to 3 carbon atoms, inclusive, and s is 0, 1, 2, or 3, the various T's being the same or different, with the proviso that not more than two T's are other than alkyl, with the further proviso that Z₃ is oxa only when R₃ and R₄ are hydrogen or methyl, being the same or different; and wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms, inclusive, or a pharmacologically acceptable cation; with the further proviso that D is ##STR8## only when Y is cis- or trans-CH═CH--.
 2. A compound according to claim 1, wherein D is ##STR9##
 3. A compound according to claim 2, wherein M₁ is ##STR10##
 4. A compound according to claim 2, wherein M₁ is ##STR11##
 5. A compound according to claim 4, wherein Y is --CH₂ CH₂ --.
 6. A compound according to claim 5, wherein Z₃ is methylene.
 7. A compound according to claim 6, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 8. A compound according to claim 5, wherein Z₃ is oxa.
 9. A compound according to claim 8, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 10. A compound according to claim 4, wherein Y is cis-CH═CH--.
 11. A compound according to claim 10, wherein Z₃ is methylene.
 12. A compound according to claim 11, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 13. A compound according to claim 10, wherein Z₃ is oxa.
 14. A compound according to claim 13, wherein s is zero or one, and T is chloro, fluoro, or trifluoromethyl.
 15. A compound according to claim 4, wherein Y is trans-CH═CH--.
 16. A compound according to claim 15, wherein Z₃ is methylene.
 17. A compound according to claim 16, wherein s is zero or one and T is chloro, fluoro, or trifluormethyl.
 18. A compound according to claim 17, wherein Z₁ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 19. A compound according to claim 18, wherein g is
 1. 20. A compound according to claim 19, wherein R₅ and R₆ are both hydrogen.
 21. A compound according to claim 20, wherein R₃ and R₄ are both hydrogen.
 22. 17-Phenyl-18,19,20-trinor-PGD₂, a compound according to claim
 21. 23. 2,2-Difluoro-17-phenyl-18,19,20-trinor-PGD₂, a compound according to claim
 21. 24. cis-4,5-Didehydro-17-phenyl-18,19,20-trinor-PGD₂, a compound according to claim
 21. 25. A compound according to claim 20, wherein R₃ and R₄ are both fluoro.
 26. 16,16-Difluoro-17-phenyl-18,19,20-trinor-PGD₂, a compound according to claim
 25. 27. A compound according to claim 17, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 28. A compound according to claim 27, wherein g is
 1. 29. A compound according to claim 28, wherein R₅ and R₆ are both hydrogen.
 30. A compound according to claim 29, wherein R₃ and R₄ are both hydrogen.
 31. 17-Phenyl-18,19,20-trinor-PGD₁, a compound according to claim
 30. 32. A compound according to claim 17, wherein Z₁ is --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, --(CH₂)₂ --O--(CH₂)_(g) --CH₂ --, or --(CH₂)₃ --O--(CH₂)_(g) --.
 33. A compound according to claim 32, wherein g is
 1. 34. A compound according to claim 33, wherein R₅ and R₆ are both hydrogen.
 35. A compound according to claim 34, wherein R₃ and R₄ are both hydrogen.
 36. 5-Oxa-17-phenyl-18,19,20-trinor-PGD₁, a compound according to claim
 35. 37. A compound according to claim 17, wherein Z₁ is ##STR12##
 38. A compound according to claim 37, wherein g is
 1. 39. A compound according to claim 38, wherein R₅ and R₆ are both hydrogen.
 40. A compound according to claim 39, wherein R₃ and R₄ are both hydrogen.
 41. 3,7-Inter-m-phenylene-4,5,6-trinor-PGD₁, a compound according to claim
 40. 42. A compound according to claim 15, wherein Z₃ is oxa.
 43. A compound according to claim 42, wherein s is 0 or 1 and T is chloro, fluoro, or trifluoromethyl.
 44. A compound according to claim 43, wherein Z₁ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --.
 45. A compound according to claim 44, wherein g is
 1. 46. A compound according to claim 45, wherein R₅ and R₆ are both hydrogen.
 47. A compound according to claim 46, wherein R₃ and R₄ are both hydrogen.
 48. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGD₂, a compound according to claim
 47. 49. A compound according to claim 43, wherein Z₁ is cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --.
 50. A compound according to claim 49, wherein g is
 3. 51. A compound according to claim 50, wherein R₅ and R₆ are both hydrogen.
 52. A compound according to claim 51, wherein R₃ and R₄ are both hydrogen.
 53. 2a,2b-Dihomo-16-phenoxy-17,18,19,20-tetranor-PGD₂, a compound according to claim
 52. 54. A compound according to claim 51, wherein R₃ and R₄ are both methyl.
 55. 16-Methyl-16-phenoxy-18,19,20-trinor-PGD₂, a compound according to claim
 54. 56. A compound according to claim 43, wherein Z₁ is cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 57. A compound according to claim 56, wherein g is
 1. 58. A compound according to claim 57, wherein R₅ and R₆ are both hydrogen.
 59. A compound according to claim 58, wherein R₃ and R₄ are both hydrogen.
 60. cis-4,5-Didehydro-16-phenoxy-17,18,19,20-tetranor-PGD₂, a compound according to claim
 59. 61. A compound according to claim 58, wherein R₃ and R₄ are both.
 62. cis-4,5-Didehydro-16-methyl-16-phenoxy-18,19,20-trinor-PGD₁, a compound according to claim
 61. 63. A compound according to claim 43, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CF₂ --.
 64. A compound according to claim 63, wherein g is
 1. 65. A compound according to claim 64, wherein R₅ and R₆ are both hydrogen.
 66. A compound according to claim 65, wherein R₃ and R₄ are both hydrogen.
 67. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGD₁, a compound according to claim
 66. 68. A compound according to claim 65, wherein R₃ and R₄ are both fluoro.
 69. 2,2,16,16-Tetrafluoro-16-phenoxy-17,18,19,20-tetranor-PGD₁, a compound according to claim
 68. 70. A compound according to claim 43, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 71. A compound according to claim 70, wherein g is
 3. 72. A compound according to claim 71, wherein R₅ and R₆ are both hydrogen.
 73. A compound according to claim 72, wherein R₃ and R₄ are both hydrogen.
 74. 16-Phenoxy-17,18,19,20-tetranor-PGD₁, a compound according to claim
 73. 75. A compound according to claim 72, wherein R₃ and R₄ are both fluoro.
 76. 16,16-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGD₁, a compound according to claim
 75. 77. A compound according to claim 43, wherein Z₁ is --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, --(CH₂)₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, or --(CH₂)₃ --O--(CH₂)_(g) --.
 78. A compound according to claim 77, wherein g is
 1. 79. A compound according to claim 78, wherein R₃, R₄, R₅, and R₆ are all hydrogen.
 80. 5-Oxa-16-phenoxy-17,18,19,20-tetranor-PGD₁, a compound according to claim
 79. 81. A compound according to claim 43, wherein Z₁ ##STR13##
 82. A compound according to claim 81, wherein g is 1 and R₃, R₄, R₅, and R₆ are all hydrogen.
 83. A compound according to claim 1, wherein D is ##STR14##
 84. A compound according to claim 1, wherein D is ##STR15##
 85. A compound according to claim 84, wherein M₁ is ##STR16##
 86. A compound according to claim 84, wherein M₁ is ##STR17##
 87. A compound according to claim 86, wherein Y is cis-CH═CH--.
 88. A compound according to claim 87, wherein Z₃ is methylene.
 89. A compound according to claim 88, wherein s is 0 or 1 and T is chloro, fluoro or trifluoromethyl.
 90. A compound according to claim 87, wherein Z₃ is oxa.
 91. A compound according to claim 90, wherein s is 0 or 1 and T is chloro, fluoro, or trifluoromethyl.
 92. A compound according to claim 86, wherein Y is trans-CH═CH--.
 93. A compound according to claim 92, wherein Z₃ is methylene.
 94. A compound according to claim 93, wherein s is 0 or 1 and T is chloro, fluoro, or trifluoromethyl.
 95. A compound according to claim 94, wherein Z₁ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 96. A compound according to claim 95, wherein g is
 1. 97. A compound according to claim 96, wherein R₅ and R₆ are both hydrogen.
 98. A compound according to claim 97, wherein R₃ and R₄ are both hydrogen.
 99. 2,2-Difluoro-17-phenyl-18,19,20-trinor-9-deoxy-9,10-didehydro-PGD₂, a compound according to claim
 98. 100. 17-Phenyl-18,19,20-trinor-9-deoxy-9,10-didehydro-PGD₂, a compound according to claim
 98. 101. cis-4,5-Didehydro-17-phenyl-18,19,20-trinor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 98. 102. A compound according to claim 94, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 103. A compound according to claim 102, wherein g is
 1. 104. A compound according to claim 103, wherein R₅ and R₆ are both hydrogen.
 105. A compound according to claim 104, wherein R₃ and R₄ are both hydrogen.
 106. 2,2-Difluoro-17-phenyl-18,19,20-trinor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 105. 107. 17-phenyl-18,19,20-trinor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 105. 108. A compound according to claim 94, wherein Z₁ is --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, --(CH₂)₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, or --(CH₂)₃ --O--(CH₂)_(g) --.
 109. A compound according to claim 108, wherein g is
 1. 110. A compound according to claim 109, wherein R₅ and R₆ are both hydrogen.
 111. A compound according to claim 110, wherein R₃ and R₄ are both hydrogen.
 112. 5-Oxa-17-phenyl-18,19,20-trinor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 111. 113. A compound according to claim 94, wherein Z₁ is ##STR18##
 114. A compound according to claim 113, wherein g is
 1. 115. A compound according to claim 114, wherein R₅ and R₆ are both hydrogen.
 116. A compound according to claim 115, wherein R₃ and R₄ are both hydrogen.
 117. 3,7-Inter-m-phenylene-4,5,6-trinor-17-phenyl-18,19,20-trinor-PGD₁, a compound according to claim
 116. 118. A compound according to claim 92, wherein Z₃ is oxa.
 119. A compound according to claim 118, wherein s is 0 or 1 and T is chloro, fluoro, or trifluoromethyl.
 120. A compound according to claim 119, wherein Z₁ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 121. A compound according to claim 120, wherein g is
 1. 122. A compound according to claim 121, wherein R₅ and R₆ are both hydrogen.
 123. A compound according to claim 122, wherein R₃ and R₄ are both hydrogen.
 124. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD₂, a compound according to claim
 123. 125. 16-Phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD₂, a compound according to claim
 123. 126. cis-4,5-Didehydro-16-phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 123. 127. A compound according to claim 119, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 128. A compound according to claim 127, wherein g is
 1. 129. A compound according to claim 128, wherein R₅ and R₆ are both hydrogen.
 130. A compound according to claim 129, wherein R₃ and R₄ are both hydrogen.
 131. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 130. 132. 16-Phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 130. 133. A compound according to claim 119, wherein Z₁ is --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, --(CH₂)₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, or --(CH₂)₃ --O--(CH₂)_(g) --.
 134. A compound according to claim 133, wherein g is
 1. 135. A compound according to claim 134, wherein R₅ and R₆ are both hydrogen.
 136. A compound according to claim 135, wherein R₃ and R₄ are both hydrogen.
 137. 5-Oxa-16-phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD₁, a compound according to claim
 136. 138. A compound according to claim 119, wherein Z₁ is ##STR19##
 139. A compound according to claim 138, wherein g is
 1. 140. A compound according to claim 139, wherein R₅ and R₆ are both hydrogen.
 141. A compound according to claim 140, wherein R₃ and R₄ are both hydrogen.
 142. 3,7-Inter-m-phenylene-16-phenoxy-17,18,19,20-tetranor-9-deoxy-9,10-didehydro-PGD.sub.1, a compound according to claim
 141. 